血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響課件

1、毛恩強(qiáng)上海交通大學(xué)醫(yī)學(xué)院附屬瑞金醫(yī)院外科ICU 外源性血管活性物質(zhì)在Sepsis微循環(huán)障礙中的作用與地位H E I血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響1毛恩強(qiáng) 外源性血管活性物質(zhì)在Sepsis微循環(huán)障礙H E I 微循環(huán)的構(gòu)成，見(jiàn)下圖H E I微循環(huán)的構(gòu)成，見(jiàn)下圖血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響2 微循環(huán)的構(gòu)成，見(jiàn)下圖H E I微循環(huán)的構(gòu)成，見(jiàn)下圖血管活膿毒血癥時(shí)微循環(huán)特點(diǎn)微小動(dòng)脈血管節(jié)律異常，成低反應(yīng)性壓力-血流自動(dòng)調(diào)節(jié)喪失兒茶酚胺和血管緊張素的縮血管作用降低(主導(dǎo))依賴內(nèi)皮的擴(kuò)血管作用喪失(大腦除外)80m 的微動(dòng)脈擴(kuò)張， 80m 的微動(dòng)脈收縮H E I【Proc Natl Aca

2、d Sci U S A 2000;97:97539758】【Baker CH, Sutton ET. (1993). Arteriolar endothelium-dependent vasodilation occurs during endotoxin. shock. Am J Physiol 264:H1118H1123.】 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響3膿毒血癥時(shí)微循環(huán)特點(diǎn)H E I【Proc Natl Acad 毛細(xì)血管灌注數(shù)量降低 微血栓形成紅細(xì)胞、白細(xì)胞變形降低、內(nèi)皮腫脹毛細(xì)血管表面積微靜脈內(nèi)皮屏障功能障礙毛細(xì)血管滲漏(蛋白、液體)PMN組織內(nèi)浸潤(rùn)Aird WC.Blo

3、od 2003; 101:376577血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響4 毛細(xì)血管灌注數(shù)量降低 Aird WC.Blood 2003不同時(shí)間點(diǎn)微循環(huán)狀態(tài) 不一相同時(shí)間點(diǎn)不同器官微循環(huán)狀態(tài)不一微循環(huán)障礙表現(xiàn)形式：時(shí)間-空間上的異常 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響5不同時(shí)間點(diǎn)微循環(huán)狀態(tài) 不一微循環(huán)障礙表現(xiàn)形式：時(shí)間-空間上的調(diào)整血管節(jié)律的活性物質(zhì)血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響6調(diào)整血管節(jié)律的活性物質(zhì)血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的受體激動(dòng)劑去甲腎上腺素:收縮阻力血管隨著劑量增加，MAP升高，但FCD(vessels/mm2, )降低0.48g/kg/min 0.65g/kg

4、/min 0.74g/kg/min 【Arnaldo Dubin.Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study. Critical Care 2009, 13:R92 (doi:10.1186/cc7922)】 收縮血管的活性物質(zhì)血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響7受體激動(dòng)劑0.48g/kg/min 0.65g/kg/毛細(xì)血管流量指數(shù)血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響8毛細(xì)血管流量指數(shù)血管活性

5、藥物對(duì)膿毒血癥微循環(huán)障礙的影響8 MAP逐漸由60、70、80升至90mmHg，去甲腎由0.18 g/kg/min逐漸加至0.41 g/kg/min全身氧輸送、皮膚PtO2 、皮膚微血管紅細(xì)胞流量顯著升高M(jìn)AP升高并不增加FCD和舌下微循環(huán)血流指數(shù)大鼠小腸肌層FCD下降至25-60%，聯(lián)合多巴酚丁胺，F(xiàn)CD正常乳酸有升高趨勢(shì)【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis. An

6、esthesia and analgesia2010110:2 (547-554) 】【The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock. Critical care medicine200937:6 (1961-1966) 】。血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響9 MAP逐漸由60、70、80升至90mmHg，去甲腎由0. 去甲腎的應(yīng)用改善微循環(huán)灌注呈劑量依賴性; 建議65mmHg后，再增加M

7、AP ，可導(dǎo)致微循環(huán)障礙SB:125ml/h逐漸增加至500ml/h血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響10 去甲腎的應(yīng)用SB:125ml/h逐漸增加至500ml/h血 去氧腎上腺素大鼠小腸肌層FCD下降至25-60%腎、內(nèi)臟、皮膚及肢體血流減少腸系膜上靜脈內(nèi)的血乳酸顯著升高【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis. Anesthesia and analgesia20

8、10110:2 (547-554) 】血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響11 去氧腎上腺素【The effects of vasoact 和受體興奮劑腎上腺素大樣本RCT，與去甲腎對(duì)MAP影響無(wú)差異，28-d和90-d死亡率無(wú)差異第一個(gè)24h，見(jiàn)心動(dòng)過(guò)速、乳酸酸中毒和增加胰島素用量 嚴(yán)重收縮小腸肌層血管，加劇微循環(huán)障礙！不建議應(yīng)用【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysi

9、s. Anesthesia and analgesia2010110:2 (547-554) 】【Myburgh JA, Higgins A, Jovanovska A, et al., CAT Study investigators. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008; 34:22262234.】 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響12 和受體興奮劑【The effects of vasoa 多巴胺：中等以上劑量，受體和1 激

10、動(dòng)劑多巴胺提高M(jìn)AP可保護(hù)腸道粘膜微循環(huán)大鼠小腸肌層FCD無(wú)顯著改變顯著增加SMA血流；其乳酸濃度不高 增加心率以及心臟負(fù)性事件發(fā)生率高于去甲腎【The effects of vasoactive drugs on intestinal functional capillary density in endotoxemic rats: intravital video-microscopy analysis. Anesthesia and analgesia2010110:2 (547-554) 】血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響13 多巴胺：中等以上劑量，受體和1 激動(dòng)劑【The ef

11、f V1、V2受體激動(dòng)劑垂體后葉素收縮全身和局部微循環(huán)消除低血壓、降低液體積聚和逆轉(zhuǎn)毛細(xì)血管滲漏冠脈血管收縮致心排量降低等內(nèi)臟血管過(guò)度收縮引起缺血壞死【Torgersen C, et al. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial. Intensive Care Med. 2010;36:5765.】 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響14 V1、V2受體激動(dòng)劑【Torgersen

12、 C, et al 膿毒血癥時(shí)狀態(tài)機(jī)體缺乏AVP感染性休克需0.067 U/min(4IU/h)方恢復(fù)至近正常水平特點(diǎn)激動(dòng)兩個(gè)受體的作用相似，選擇性差半衰期是6min、作用維持30-60min 【Torgersen C, et al. Comparing two different arginine vasopressin doses in advanced vasodilatory shock: a randomized, controlled, open-label trial. Intensive Care Med. 2010;36:5765.】 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響1

13、5 膿毒血癥時(shí)狀態(tài)【Torgersen C, et al. C 特利加壓素(Terlipressin)V1a收縮血管為主要作用降低毛細(xì)血管滲漏、逆轉(zhuǎn)低血壓半衰期6小時(shí)，療效2-10小時(shí)持續(xù)緩慢靜推(1.3g/kg/h)，最大劑量是2g/kg/h 負(fù)性心血管作用，需多巴酚丁胺抵消【Ertmer C. Current place of vasopressin analogues in the treatment of septic shock. Curr Infect Dis Rep 2008;10:362367.】【Ryckwaert F.Terlipressin, a provasopress

14、in drug exhibits direct vasoconstrictor properties: consequences on heart perfusion and performance. Crit Care Med 2009;37:876881. 】 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響16 特利加壓素(Terlipressin)【Ertmer C. 血管加壓素的應(yīng)用建議在兒茶酚胺抵抗時(shí)再給予應(yīng)用劑量：恢復(fù)生理水平精氨酸加壓素的劑量 0.03 0.067 U/min(4IU/h)特利加壓素， 1.3g/kg/h，最大劑量是2g/kg/h 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響1

15、7 血管加壓素的應(yīng)用血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響17 縮血管物質(zhì)的作用提高M(jìn)AP，儲(chǔ)備毛細(xì)血管前灌注壓力降低體液積聚和逆轉(zhuǎn)毛細(xì)血管滲漏恢復(fù)毛細(xì)血管灌注負(fù)性作用皮膚、內(nèi)臟阻力血管和微循環(huán)過(guò)度收縮心臟負(fù)性作用 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響18 縮血管物質(zhì)的作用 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響1擴(kuò)張血管的活性物質(zhì)NO供體硝酸甘油(NTG)：改善微循環(huán)灌注，但褒貶不一主要擴(kuò)張靜脈和微小動(dòng)脈降低肺動(dòng)脈壓、恢復(fù)組織灌注和提高生存率擴(kuò)容穩(wěn)定后，硝酸甘油并不能改善微循環(huán)，甚至對(duì)存活率有負(fù)性作用【Lamontagne F, Meade M, Ondiveeran HK, et al.

16、 Nitric oxide donors in sepsis: a systematic review of clinical and in vivo preclinical data. Shock 2008;30:653659.】 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響19擴(kuò)張血管的活性物質(zhì)NO供體【Lamontagne F, Me【Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resus

17、citation protocol: A double-blind randomized placebo controlled trial. Crit Care Med 2010; 38:93100.】 60天存活率也顯著降低P=0.08P=0.09NTG ,2mg 持續(xù)靜推30分鐘，然后23.5h持續(xù)2mg/h。維持MAP60mmHg血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響20【Effects of nitroglycerin on s 死亡率升高的原因NTG不是NO前體長(zhǎng)期應(yīng)用，血管收縮占主導(dǎo)(兒茶酚胺、加壓素、醛固酮和腎素水平升高)NTG打開(kāi)線粒體的滲透轉(zhuǎn)運(yùn)孔致其產(chǎn)生的氧自由基漏出線粒體的

18、衰竭與NTG的高死亡率相關(guān)【Parker JD, Farrell B, Fenton T, et al: Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin. Circulation 1991; 84:23362345.】【Gori T, Daiber A, Di Stolfo G, et al: Nitroglycerin causes mitochondrial reactive oxygen species production: In vitro mechanist

19、ic insights. Can J Cardiol 2007; 23:990992】血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響21 死亡率升高的原因【Parker JD, Farrell B L-精氨酸大循環(huán)穩(wěn)定后應(yīng)用改善微循環(huán)血流單用即可改善微循環(huán)紊亂聯(lián)合血管加壓素對(duì)改善微循環(huán)有疊加效應(yīng)Nakajima Y, Baudry N, Duranteau J, et al. Effects of vasopressin, norepinephrine and L-arginine on intestinal microcirculation in endotoxemia. Crit Care Med

20、 2006; 34:17521757】【De Backer D. L-arginine and vasopressor agents: when antagonists have unexpected synergistic effects. Crit Care Med 2006; 34:18471849.】血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響22 L-精氨酸Nakajima Y, Baudry N, Du受體興奮劑多培沙明 有很強(qiáng)2-受體興奮作用， 1和DA1、DA2較弱顯著擴(kuò)張動(dòng)脈血管，能增加心肌、腎臟、肝臟、骨骼肌的血流量，降低心臟后負(fù)荷心肌收縮力加強(qiáng)，心率加快，并有輕微排鈉利尿作用；

21、0.5ug/kg/min開(kāi)始應(yīng)用Effects of Dopamine, Dobutamine, and Dopexamine on Microcirculatory Blood Flow in the Gastrointestinal Tract during Sepsis and Anesthesia. Anesthesiology 2004; 100:118897血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響23受體興奮劑Effects of Dopamine, Dobu 受體阻斷藥物受體阻斷藥，酚妥拉明和酚芐明解除去甲腎導(dǎo)致的微血管過(guò)度收縮M受體阻斷藥:山莨菪堿、東崀菪堿、鹽酸戊乙喹醚(阻斷M

22、1、M3)解除毛細(xì)血管前括約肌痙攣抑制PAF-1和TF的激活【Effects of penehyclidine hydrochloride on the splanchnic perfusion of patients with septic shock. Chinese Critical Care Medicine200820:3 (183-186) 】【Anisodamine counteracts lipopolysaccharide-induced tissue factor and plasminogen activator inhibitor-1 expression in hum

23、an endothelial cells: Contribution of the NF-B pathway. J Vas Res200138:1 (13-19) 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響24 受體阻斷藥物【Effects of penehyclidi 抗氧化劑：Vit C恢復(fù)依賴內(nèi)皮的血管節(jié)律(舒張和收縮)血管舒張作用(NO)抑制iNOS活性增加eNOS的活性抑制內(nèi)皮細(xì)胞內(nèi)的NADPH酶活性阻止NO氧化【Septic impairment of capillary blood flow requires nicotinamide adenine dinucleotide pho

24、sphate oxidase but not nitric oxide synthase and is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism. Crit Care Med 2008; 36:23552362】【 Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Cr

25、it Care Med 2005; 33:18231828.】 同時(shí)收縮與擴(kuò)張血管的活性物質(zhì)血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響25 抗氧化劑：Vit C【Septic impairment 收縮血管作用提高兒茶酚胺的敏感性去甲腎上腺素和血管緊張素【Lehr1 HA. Eur J Med Res 2006;11: 516-526】【Nualart FJ. J Biol Chem 2003; 278:10128101331】15例感染性休克病人(肺部感染和腹腔感染)去甲腎0.3g/kg/min血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響26 收縮血管作用【Lehr1 HA. Eur J Med Re

26、增加氧攝取的活性物質(zhì)血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響27增加氧攝取的活性物質(zhì)血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響2 降低PMN與內(nèi)皮的粘附多巴酚丁胺主要興奮1、對(duì)2及受體作用相對(duì)弱增加心臟指數(shù)和全身血流抑制PMN粘附到血管內(nèi)皮或促進(jìn)內(nèi)皮完整性增加微循環(huán)血流 【Secchi A, Ortanderl JM, Schmidt W, et al. Effects of dobutamine and dopexamine on hepatic micro- and macrocirculation during experimental endotoxemia: an intravital m

27、icroscopic study in the rat. Crit Care Med 2001; 29:597600.】 【Birnbaum J, Klotz E, Spies CD, et al. Effects of dopexamine on the intestinal microvascular blood flow and leukocyte activation in a sepsis model in rats. Crit Care 2006; 10:R117.】 血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響28 降低PMN與內(nèi)皮的粘附【Secchi A, Ortande Vit C封閉內(nèi)皮細(xì)胞、降低PMN粘附、降低微血栓形成降低毛細(xì)血管滲漏減少液體復(fù)蘇的液體量改善組織水腫縮短毛管和細(xì)胞的距離Crit Care Med. 2005;33(8):1823-8.血管活性藥物對(duì)膿毒血癥微循環(huán)障礙的影響29 Vit CCrit Care Med. 2005;33(8 抗凝 降低微血栓形成增加FCD人重組活化蛋白C不能降低28天死亡率顯著增加出血率APC